Itraconazole, a P-Glycoprotein and CYP3A4 Inhibitor, Markedly Raises the Plasma Concentrations and Enhances the Renin-Inhibiting Effect of Aliskiren

Tapaninen, Tuija; Backman, Janne T.; Kurkinen, Kaisa J.; Neuvonen, Pertti J.; Niemi, Mikko

doi:10.1177/0091270010365885

Cited by 55 publications

(61 citation statements)

References 42 publications

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“…Importantly, colchicine was also identified as the sole false negative of highly permeable BDDCS class 1 compounds that were P-gp substrates when predicting CNS exposure (24). Aliskiren and cefoperazone are poorly permeable and eliminated in the bile (39,40), although we initially classified them as extensively metabolized/highly permeable. We utilized aliskiren as an external validation compound in our model predicting when biliary elimination is the major route of elimination and adjusted its class to class 3 for further studies.…”

Section: Corrections Recognized By Discrepancies Between Permeabilitymentioning

confidence: 99%

BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs

Hosey-Cojocari

Chan

Benet

2015

AAPS J

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Abstract. The biopharmaceutics drug disposition classification system was developed in 2005 by Wu and Benet as a tool to predict metabolizing enzyme and drug transporter effects on drug disposition. The system was modified from the biopharmaceutics classification system and classifies drugs according to their extent of metabolism and their water solubility. By 2010, Benet et al. had classified over 900 drugs. In this paper, we incorporate more than 175 drugs into the system and amend the classification of 13 drugs. We discuss current and additional applications of BDDCS, which include predicting drug-drug and endogenous substrate interactions, pharmacogenomic effects, food effects, elimination routes, central nervous system exposure, toxicity, and environmental impacts of drugs. When predictions and classes are not aligned, the system detects an error and is able to self-correct, generally indicating a problem with initial class assignment and/or measurements determining such assignments.

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Section: Corrections Recognized By Discrepancies Between Permeabilitymentioning

confidence: 99%

BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs

Hosey-Cojocari

Chan

Benet

2015

AAPS J

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“…Aliskiren plasma and urine concentrations were quantified using an Applied Biosystems SCIEX Q Trap LC/MS/MS system (Sciex Division of MDS, Toronto, Ontario, Canada) [31]. Acebutolol served as an internal standard.…”

Section: Determination Of Aliskiren Concentrations and Renin Activitymentioning

confidence: 99%

“…3,3',4',5,6,7,8-heptamethoxyflavone, tangeritin and nobiletin, have been shown to inhibit P-glycoprotein in vitro [44][45][46]. However, inhibition of the P-glycoprotein should increase, not decrease, the plasma concentrations of aliskiren [31]. Therefore, it appears unlikely that inhibition of the P-glycoprotein would play an important role in the interaction between orange juice and aliskiren.…”

Section: Figurementioning

confidence: 99%

“…These characteristics render it susceptible to transporter-mediated drug interactions and a good candidate for a probe substrate for transporters in vivo. In addition to the effects of grapefruit juice, aliskiren has also been found to be susceptible to induction and inhibition of the P-glycoprotein efflux transporter by rifampicin and itraconazole, respectively [30,31].…”

Section: Introductionmentioning

confidence: 99%

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Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren

Tapaninen

Neuvonen

Niemi

2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Aliskiren is an antihypertensive drug with a low oral bioavailability.• Aliskiren is eliminated primarily unchanged into bile, and it is a substrate of the organic anion transporting polypeptide 2B1 (OATP2B1) influx transporter, the P‐glycoprotein efflux transporter and cytochrome P450 3A4.• Flavonoids in orange and apple juice have been shown to inhibit OATP2B1 in vitro.WHAT THIS STUDY ADDS• Orange juice and apple juice markedly reduce the plasma concentrations of aliskiren probably by inhibiting its OATP2B1‐mediated intestinal absorption.• Concomitant intake of aliskiren with orange or apple juice is best avoided.AIM The aim of this study was to investigate the effects of orange juice and apple juice on the pharmacokinetics and pharmacodynamics of aliskiren.METHODS In a randomized crossover study, 12 healthy volunteers ingested 200 ml of orange juice, apple juice or water three times daily for 5 days. On day 3, they ingested a single 150‐mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h, its excretion into urine up to 12 h and plasma renin activity up to 24 h.RESULTS Orange and apple juice reduced aliskiren peak plasma concentrations by 80% (95% CI 63%, 89%, P < 0.001) and 84% (95% CI 72%, 91%, P < 0.001), and the area under the plasma aliskiren concentration–time curve (AUC) by 62% (95% CI 47%, 72%, P < 0.001) and 63% (95% CI 46%, 74%, P < 0.001), respectively, but had no significant effect on its elimination half‐life or renal clearance. The decreases in aliskiren AUC by orange and apple juice correlated with aliskiren AUC during the water phase (r= 0.98, P < 0.001). Plasma renin activity was 87% and 67% higher at 24 h after aliskiren during the orange juice and apple juice phases, respectively, than during the water phase (P < 0.05).CONCLUSIONS Orange juice and apple juice greatly reduce the plasma concentrations and renin‐inhibiting effect of aliskiren, probably by inhibiting its OATP2B1‐mediated influx in the small intestine. Concomitant intake of aliskiren with orange or apple juice is best avoided.

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“…We 8 considered that there would be no effect on the purity of the plasma membrane fraction 9 even if the pellet contained the cellular structures, because the obtained pellet was 10 subsequently homogenized by rotated strokes with a Potter-Elvehjem homogenizer and 11 nitrogen cavitation according to our previous report. 34 The isolated mouse intestinal 12 epithelial cells were homogenized by 15 up-and-down rotated strokes (1,000 rpm) of a 13 Potter-Elvehjem homogenizer in hypotonic buffer [10 mM Tris-HCl (pH 7.4), 10 mM 14 NaCl, 1.5 mM MgCl2, 1 mM phenylmethylsulfonyl fluoride, and 1 % (v/v) protease 15 inhibitor cocktails (Sigma Chemical Co., St. Louis, MO, USA)]. The homogenates were 16 kept in ice for 30 min, then homogenized again with 20 up-and-down rotated strokes 17 (1,000 rpm) on ice, and finally subjected to nitrogen cavitation at 450 psi for 15 min at 18 4°C.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Targeted Absolute Proteomics of Transporters and Pharmacoproteomics-Based Reconstruction of P-Glycoprotein Function in Mouse Small Intestine

et al. 2016

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The purpose of this study was to investigate whether a pharmacokinetic model integrating in vitro mdr1a efflux activity (which we previously reported) with in vitro/in vivo differences in protein expression level can reconstruct intestinal mdr1a function. In situ intestinal permeability-surface area product ratio between wild-type and mdr1a/1b (-/-) mice is one of the parameters used to describe intestinal mdr1a function. The reconstructed ratios of six mdr1a substrates (dexamethasone, digoxin, loperamide, quinidine, verapamil, vinblastine) and one nonsubstrate (diazepam) were consistent with the observed values reported by Adachi et al. within 2.1-fold difference. Thus, intestinal mdr1a function can be reconstructed by our pharmacoproteomic modeling approach. Furthermore, we evaluated regional differences in protein expression levels of mouse intestinal transporters. Sixteen (mdr1a, mrp4, bcrp, abcg5, abcg8, glut1, 4f2hc, sglt1, lat2, pept1, mct1, slc22a18, ostβ, villin1, Na(+)/K(+)-ATPase, γ-gtp) out of 46 target molecules were detected by employing our established quantitative targeted absolute proteomics technique. The protein expression amounts of mdr1a and bcrp increased progressively from duodenum to ileum. Sglt1, lat2, and 4f2hc were highly expressed in jejunum and ileum. Mct1 and ostβ were highly expressed in ileum. The quantitative expression profiles established here should be helpful to understand and predict intestinal transporter functions.

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Itraconazole, a P-Glycoprotein and CYP3A4 Inhibitor, Markedly Raises the Plasma Concentrations and Enhances the Renin-Inhibiting Effect of Aliskiren

Cited by 55 publications

References 42 publications

BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs

BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs

Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren

Quantitative Targeted Absolute Proteomics of Transporters and Pharmacoproteomics-Based Reconstruction of P-Glycoprotein Function in Mouse Small Intestine

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